Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study.

BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial.

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124-159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir. FUNDING: Penta Foundation, ViiV Healthcare, and UK Medical Research Council.

Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial.

Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm3 (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m2 (95% CI: 0.3, 1.0; p < 0.001)]. Interpretation: In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. Funding: Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.

Microbiota in the oral cavity of school-age children with HIV who started antiretroviral therapy at young ages in South Africa.

BACKGROUND: Infancy is an important developmental period when the microbiome is shaped. We hypothesized that earlier antiretroviral therapy (ART) initiation would attenuate HIV effects on microbiota in the mouth. METHODS: Oral swabs were collected from 477 children with HIV (CWH) and 123 children without (controls) at two sites in Johannesburg, South Africa. CWH had started ART less than 3 years of age; 63% less than 6 months of age. Most were well controlled on ART at median age 11 years when the swab was collected. Controls were age-matched and recruited from the same communities. Sequencing of V4 amplicon of 16S rRNA was done. Differences in microbial diversity and relative abundances of taxa were compared between the groups. RESULTS: CWH had lower alpha diversity than controls. Genus-level abundances of Granulicatella, Streptococcus, and Gemella were greater and Neisseria and Haemophilus less abundant among CWH than controls. Associations were stronger among boys. Associations were not attenuated with earlier ART initiation. Shifts in genus-level taxa abundances in CWH relative to controls were most marked in children on lopinavir/ritonavir regimens, with fewer shifts seen if on efavirenz ART regimens. CONCLUSION: A distinct profile of less diverse oral bacterial taxa was observed in school-aged CWH on ART compared with uninfected controls suggesting modulation of microbiota in the mouth by HIV and/or its treatments. Earlier ART initiation was not associated with microbiota profile. Proximal factors, including current ART regimen, were associated with contemporaneous profile of oral microbiota and may have masked associations with distal factors such as age at ART initiation.

Disclosure to South African children about their own HIV status over time.

Disclosure to children living with HIV (CLHIV) about their own status is associated with positive outcomes such as treatment adherence, but prior cross-sectional studies in sub-Saharan Africa report disclosure rates of <50%. This study aims to assess pediatric disclosure over time. 548 CLHIV were followed from 2/2013-4/2018 in Johannesburg, South Africa. Cumulative incidence of disclosure was calculated with Kaplan-Meier analysis, and disclosure characteristics assessed with a Cox model. By end of follow-up, cumulative disclosure was 70.3% (95% confidence interval: 60.0-79.9). Median age at disclosure was 9 years (range: 3-13). Baseline predictors of disclosure included older child age and the child having a history of going hungry. Prior to disclosure, 98.0% of caregivers who disclosed had conversed with their child about their illness or an HIV-related topic, or their child had asked about HIV, versus 88.6% of caregivers who never disclosed. While many children did not receive disclosure during this relatively large, longitudinal study of South African CLHIV, caregivers who had not yet disclosed may have been preparing to do so by discussing their child's health or HIV generally with their child. This highlights the need for clinicians to consistently support caregivers throughout the incremental disclosure process.

Experiences of South African caregivers disclosing to their children living with HIV: Qualitative investigations.

Awareness of Human Immunodeficiency Virus (HIV) status improves health outcomes in children living with HIV, yet caregivers often delay disclosure. This qualitative investigation explored, through observation, how 30 caregivers responded to a HIV Disclosure study conducted between 2017 and 2020 at Chris Hani Baragwanath Academic Hospital, Soweto, South Africa. Caregivers were assisted in disclosing to their children, aged 7-13 years; followed by a sub-sample of caregivers providing in-depth interviews to elaborate on findings.1) Barriers to disclosure included: caregivers being ill equipped, the fear of negative consequences and children considered lacking emotional or cognitive readiness. 2) Deflecting diagnosis from their children and the need for medication, motivated caregivers to disclosure. 3) Apprehension was evident during disclosure; however, overall disclosure was a positive experience with the support of the healthcare providers. These results highlight the significant role healthcare providers' play in supporting caregivers through the disclosure process.

Machine learning outperformed logistic regression classification even with limit sample size: A model to predict pediatric HIV mortality and clinical progression to AIDS.

Logistic regression (LR) is the most common prediction model in medicine. In recent years, supervised machine learning (ML) methods have gained popularity. However, there are many concerns about ML utility for small sample sizes. In this study, we aim to compare the performance of 7 algorithms in the prediction of 1-year mortality and clinical progression to AIDS in a small cohort of infants living with HIV from South Africa and Mozambique. The data set (n = 100) was randomly split into 70% training and 30% validation set. Seven algorithms (LR, Random Forest (RF), Support Vector Machine (SVM), K-Nearest Neighbor (KNN), Naïve Bayes (NB), Artificial Neural Network (ANN), and Elastic Net) were compared. The variables included as predictors were the same across the models including sociodemographic, virologic, immunologic, and maternal status features. For each of the models, a parameter tuning was performed to select the best-performing hyperparameters using 5 times repeated 10-fold cross-validation. A confusion-matrix was built to assess their accuracy, sensitivity, and specificity. RF ranked as the best algorithm in terms of accuracy (82,8%), sensitivity (78%), and AUC (0,73). Regarding specificity and sensitivity, RF showed better performance than the other algorithms in the external validation and the highest AUC. LR showed lower performance compared with RF, SVM, or KNN. The outcome of children living with perinatally acquired HIV can be predicted with considerable accuracy using ML algorithms. Better models would benefit less specialized staff in limited resources countries to improve prompt referral in case of high-risk clinical progression.

Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial.

BACKGROUND: Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. METHODS: ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and <14 kg). Children weighing less than 14 kg starting first-line or second-line ART were enrolled in seven HIV treatment centres in South Africa, Uganda, and Zimbabwe. Randomisation, which was computer generated by the trial statistician, was stratified by first-line or second-line ART and three weight bands. Dispersible 5 mg dolutegravir was dosed according to WHO weight bands. The primary outcome was the Kaplan-Meier estimated proportion of children with virological or clinical failure by 96 weeks, defined as: confirmed viral load of at least 400 copies per mL after week 36; absence of virological suppression by 24 weeks followed by a switch to second-line or third-line ART; all-cause death; or a new or recurrent WHO stage 4 or severe WHO stage 3 event. The primary outcome was assessed by intention to treat in all randomly assigned participants. A primary Bayesian analysis of the difference in the proportion of children meeting the primary outcome between treatment groups incorporated evidence from the higher weight cohort (≥14 kg) in a prior distribution. A frequentist analysis was also done of the lower weight cohort (<14 kg) alone. Safety analyses are presented for all randomly assigned children in this study (<14 kg cohort). ODYSSEY is registered with ClinicalTrials.gov, NCT02259127. FINDINGS: Between July 5, 2018, and Aug 26, 2019, 85 children weighing less than 14 kg were randomly assigned to receive dolutegravir (n=42) or standard of care (n=43; 32 [74%] receiving protease inhibitor-based ART). Median age was 1·4 years (IQR 0·6-2·0) and median weight 8·1 kg (5·4-10·0). 72 (85%) children started first-line ART and 13 (15%) started second-line ART. Median follow-up was 124 weeks (112-137). By 96 weeks, treatment failure occurred in 12 children in the dolutegravir group (Kaplan-Meier estimated proportion 31%) versus 21 (48%) in the standard-of-care group. The Bayesian estimated difference in treatment failure (dolutegravir minus standard of care) was -10% (95% CI -19% to -2%; p=0·020), demonstrating superiority of dolutegravir. The frequentist estimated difference was -18% (-36% to 2%; p=0·057). 15 serious adverse events were reported in 11 (26%) children in the dolutegravir group, including two deaths, and 19 were reported in 11 (26%) children in the standard-of-care group, including four deaths (hazard ratio [HR] 1·08 [95% CI 0·47-2·49]; p=0·86). 36 adverse events of grade 3 or higher were reported in 19 (45%) children in the dolutegravir group, versus 34 events in 21 (49%) children in the standard-of-care group (HR 0·93 [0·50-1·74]; p=0·83). No events were considered related to dolutegravir. INTERPRETATION: Dolutegravir-based ART was superior to standard of care (mainly protease inhibitor-based) with a lower risk of treatment failure in infants and young children, providing support for global dispersible dolutegravir roll-out for younger children and allowing alignment of adult and paediatric treatment. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

Optimizing the World Health Organization algorithm for HIV vertical transmission risk assessment by adding maternal self-reported antiretroviral therapy adherence.

BACKGROUND: The World Health Organization (WHO) risk assessment algorithm for vertical transmission of HIV (VT) assumes the availability of maternal viral load (VL) result at delivery and early viral control 4 weeks after initiating antiretroviral treatment (ART). However, in many low-and-middle-income countries, VL is often unavailable and mothers' ART adherence may be suboptimal. We evaluate the inclusion of the mothers' self-reported adherence into the established WHO-algorithm to identify infants eligible for enhanced post-natal prophylaxis when mothers' VL result is not available at delivery. METHODS: We used data from infants with perinatal HIV infection and their mothers enrolled from May-2018 to May-2020 in Mozambique, South Africa, and Mali. We retrospectively compared the performance of the WHO-algorithm with a modified algorithm which included mothers' adherence as an additional factor. Infants were considered at high risk if born from mothers without a VL result in the 4 weeks before delivery and with adherence <90%. RESULTS: At delivery, 143/184(78%) women with HIV knew their status and were on ART. Only 17(12%) obtained a VL result within 4 weeks before delivery, and 13/17(76%) of them had VL ≥1000 copies/ml. From 126 women on ART without a recent VL result, 99(79%) had been on ART for over 4 weeks. 45/99(45%) women reported suboptimal (< 90%) adherence. A total of 81/184(44%) infants were classified as high risk of VT as per the WHO-algorithm. The modified algorithm including self-adherence disclosure identified 126/184(68%) high risk infants. CONCLUSIONS: In the absence of a VL result, mothers' self-reported adherence at delivery increases the number of identified infants eligible to receive enhanced post-natal prophylaxis.

Children's Positive and Negative Emotional Responses to an HIV Disclosure Study in South Africa.

The benefits of HIV status disclosure to children is widely cited. However, few studies have reported how children respond to the process in a longitudinal fashion. This paper describes children's responses, as documented by healthcare providers (HCPs), during a longitudinal disclosure study conducted at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Two HCPs facilitating disclosure recorded observations of 30 participating children (60% female), aged 7-13 years. Participants attended an average of six disclosure counseling sessions over 78 weeks. Observations documented by HCPs included the child's behavior and expressed emotions during the disclosure counseling sessions. The data was analyzed using content analysis. Mixed responses were observed in children who received full disclosure (27/30), with more children responding with strong negative emotions (16/27). However, 10 of those responded well to reassurance, and emotionally improved over subsequent sessions. Improvements were also observed in the communication and relationship between caregivers and children (17/30). Although most children understood the disclosure content (17/30), many were avoidant of the topic of HIV (16/30). With the understanding of the complex range of emotions elicited by HIV disclosure, we can better prepare HCPs on what to anticipate and train caregivers to further manage negative responses post-disclosure. This in turn may lead to more positive experiences of disclosure and the child's healthy acceptance of their HIV status.

Impact of Disclosure over Time on the Emotional Well-Being of Children with Perinatally Acquired HIV Infection in South Africa.

OBJECTIVE: The aim of this study was to describe the disclosure process in children with perinatally acquired HIV infection (PHIV+) and its impact on their emotional well-being and adherence to antiretroviral therapy (ART) in South Africa. METHODS: This prospective cohort study followed PHIV+ children aged 7 to 13 years attending counseling over 18 months. Standardized disclosure tools were used by a counselor with both child and caregiver present. Assessments included the Child Behavior Checklist (CBCL), Vineland Adaptive Behavior Scale (VABS), Child Depression Inventory (CDI), and Revised Children's Manifest Anxiety Scale (RCMAS). Adherence to ART was recorded through pharmacy pill returns. Changes over time and their differences from baseline were assessed by linear mixed models. RESULTS: Thirty children with median age 10 years (interquartile range [IQR]: 9.0-11.0) were enrolled. The median time to disclosure was 48 weeks (IQR: 48.0-54.6). There was a significant decrease from baseline (p < 0.0001) and over time (p = 0.0037) in the total CDI score. A positive trend in the changes from baseline and over time was observed for internalizing (p values < 0.0001) and externalizing (p values < 0.0001) CBCL scales and Total Anxiety score of the RCMAS (p < 0.0001 and p < 0.0002, respectively). Only the Defensiveness median T-score increased during the follow-up (p = 0.004) and in the change from baseline (p = 0.0005). The adaptive (p = 0.0092) and maladaptive (p < 0.0001) scores of the VABS showed a decrease from baseline. ART adherence remained high throughout this study. CONCLUSION: Disclosure does not worsen the child's emotional well-being and adherence to ART over time. This study adds to research from low- and middle-income countries to alleviate fears that disclosure may have an adverse outcome on children with PHIV+.

Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).

The Etiology of Pneumonia in HIV-1-infected South African Children in the Era of Antiretroviral Treatment: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: HIV-1 infection predisposes to an increased burden of pneumonia caused by community-acquired and opportunistic pathogens. METHODS: Within the context of the Pneumonia Etiology Research for Child Health case-control study of under 5 pneumonia, we investigated the etiology of World Health Organization-defined severe/very severe pneumonia requiring hospitalization in South African HIV-infected children. Nasopharyngeal-oropharyngeal swabs and blood, collected from cases and age- and season-matched HIV-infected controls attending outpatient antiretroviral therapy (ART) clinics, were analyzed using molecular diagnostic methods. Cases were also investigated for tuberculosis. Etiologic fractions among cases with radiologically confirmed pneumonia were derived using Bayesian analytic techniques. RESULTS: Of 115 HIV-infected cases, 89 (77.4%) had radiologically confirmed pneumonia. Severe immunosuppression (adjusted odds ratio, 32.60; 95% confidence interval, 7.25-146.64) was significantly associated with radiologically confirmed pneumonia. Cotrimoxazole prophylaxis (46.4% vs. 77.4%) and ART (28.2% vs. 83.1%) coverage were significantly lower in cases compared with ART-clinic controls. An etiologic agent was identified in 99.0% of the radiologically confirmed cases. The 'top 4' pathogens associated with radiologically confirmed pneumonia were Pneumocystis jirovecii [23.0%; 95% credible interval (CrI), 12.4%-31.5%], Staphylococcus aureus (10.6%; 95% CrI, 2.2%-20.2%), pneumococcus (9.5%; 95% CrI, 2.2%-18.0%) and respiratory syncytial virus (9.3%; 95% CrI, 2.2%-14.6%). Bacteremia (6.7%) and in-hospital death (10.1%) were frequent among those with radiologically confirmed disease. CONCLUSIONS: Pneumocystis jirovecii, S. aureus, pneumococcus and respiratory syncytial virus contribute a considerable burden of radiologically confirmed pneumonia in South African HIV-infected children under 5 years. Expediting access to ART and cotrimoxazole prophylaxis would decrease the burden of pneumonia in these children.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial.

BACKGROUND: Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per µL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUCtau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir Ctau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0-93·0] for AUCtau and 65·4% [58·3-73·3] for Ctau in adolescents; GLSM 125% [90% CI 117-134] for AUCtau and 88·9% [80·6-98·0] for Ctau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance. INTERPRETATION: In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population. FUNDING: Gilead Sciences.

Recovery of HIV encephalopathy in perinatally infected children on antiretroviral therapy.

AIM: To describe the trajectory of clinical signs in children who developed human immunodeficiency virus encephalopathy (HIVE) after starting early antiretroviral therapy (ART). METHOD: This was a retrospective case-cohort description of HIVE among Cape Town participants from the Children with HIV Early AntiRetroviral treatment (CHER) trial. Criteria for HIVE diagnosis were at least two of: (1) acquired central motor deficit, (2) impaired brain growth, and (3) failure to attain or loss of developmental milestones in the absence of an alternative aetiology. RESULTS: Of 133 surviving participants who initiated ART at a median age of 9 weeks and who were followed until a median age of 6 years, 20 (12%) developed HIVE at a median age 31 months (interquartile range 19-37). In these, the first neurological deterioration was noticed at a median age of 19 months, when 16 were on ART and nine had undetectable HIV viral load for a median of 12 months. Signs of upper motor neurons were present in 18, of whom 12 resolved and four had persistent spastic diplegia; 19 had motor delay, of whom 14 resolved; 12 had language delay, of whom 11 resolved; and 16 had impaired brain growth, of whom only five recovered. For the 16 participants already on ART at HIVE diagnosis, regimens were not altered in response to diagnosis. INTERPRETATION: HIVE may occur despite early ART initiation and virological suppression and then resolve on unchanged ART, most likely as intrathecal inflammation subsides. WHAT THIS PAPER ADDS: Despite suppressive antiretroviral therapy, children can develop human immunodeficiency virus encephalopathy, The most common manifestations are motor deficits and impaired brain growth. Most experience improvement, with many resolving without additional intervention.

Behavioral Functioning and Quality of Life in South African Children Living with HIV on Antiretroviral Therapy.

This study examined behavioral functioning and quality of life in South African children living with perinatally acquired HIV. Compared with controls, children living with perinatally acquired HIV had a higher mean total difficulties score assessed by the Strengths and Difficulties Questionnaire and lower mean quality of life scores assessed by the Pediatric Quality of Life Inventory.

Abacavir Exposure in Children Cotreated for Tuberculosis with Rifampin and Superboosted Lopinavir-Ritonavir.

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.).

Negative Diagnostic PCR Tests in School-Aged, HIV-Infected Children on Antiretroviral Therapy Since Early Life in Johannesburg, South Africa.

BACKGROUND: Younger age at antiretroviral therapy (ART) initiation has been associated with smaller HIV reservoirs. We investigated whether younger age of ART initiation is associated with testing negative and weaker signal on a standard HIV diagnostic test in treated children. METHODS: At exit from a longitudinal study at 2 sites in Johannesburg, South Africa, 316 school-aged, HIV-infected children on continuous ART started at a median age of 6.3 months, were tested with standard total nucleic acid PCR used for infant diagnosis. All negative results were repeated. Simultaneous viral load (VL) and CD4 T-cell counts/percentages, along with data collected over the prior 4 years, were used in multivariable regression to predict negative PCR results and higher cycle threshold (Ct) values (weaker signal). RESULTS: Seven children (2.2%, 95% confidence interval: 0.6 to 3.8) in the full cohort had negative PCR results; all 7 were in a subset of 102 (6.9%, 95% confidence interval: 2.0 to 11.8) who had initiated ART at age 0-4 months and had VL <50 copies/mL at the time of PCR testing. Only one repeat tested as negative. Younger age at ART initiation, VL <50 copies/mL at time of test, sustained VL <400 copies/mL, lower CD4 T-cell counts, and ever treated with efavirenz were significant predictors of weaker signal on the diagnostic test. CONCLUSIONS: In a small proportion of children who start ART in the first months of life and remain on continuous therapy, standard diagnostic HIV PCR tests may result as negative. Repeat testing may resolve uncertainty of diagnosis.

Educational delays among children living with perinatally-acquired HIV in Johannesburg, South Africa.

Little is known about how growing up with HIV impacts educational outcomes in sub-Saharan African children. We evaluated if South African children living with HIV (CLWH) were in the appropriate school grade-for-age compared to uninfected control children. We observed higher rates of not being in the correct grade-for-age in CLWH compared with controls (OR 3.32, 95% CI: 2.07-5.34), adjusted for study site, sex, whether the child's biological father was alive, and caregiver education. Initiation of ART before 6 months of age reduced but did not eliminate this association. Whether these associations are due to biological factors or other social and environmental determinants, and how best to support CLWH to achieve educational goals, warrants further investigation.

Mitochondrial Impairment in Well-Suppressed Children with Perinatal HIV-Infection on Antiretroviral Therapy.

Mitochondrial impairment is reported in HIV-infected children receiving antiretroviral therapy (ART), as well as those naive to ART. Whether mitochondrial function recovers with early initiation of ART and sustained viral suppression on long-term ART is unclear. In this study, we evaluate mitochondrial markers in well-suppressed perinatally HIV-infected children initiated on ART early in life. We selected a cross-sectional sample of 120 HIV-infected children with viral load <400 copies/mL and 60 age-matched uninfected children (22 HIV-exposed uninfected) enrolled in a cohort study in Johannesburg, South Africa. Complex IV (CIV) and citrate synthase (CS) activity were measured by spectrophotometry. Mitochondrial DNA (mtDNA) content relative to nuclear DNA (nDNA) was measured by quantitative real-time polymerase chain reaction and expressed as copies/nDNA. Mitochondrial markers were impaired in HIV-infected children, including lower mean CIV activities [1.76 vs. 1.40 optical densities (OD)/min], higher risk of a CIV/CS ratio ≤0.22 (third quartile; odds ratio = 3.03, 95% confidence interval: 1.38-6.66), and lower mtDNA content. Children with shorter versus longer ART duration (<6.3 vs. ≥6.3 years) had lower means of CIV activity (1.22-1.58 OD/min) and mtDNA content (386-907 copies/nDNA). There were no differences in mitochondrial markers between children who started ART earlier (<6 months) or later (6-24 months). CIV activity was impaired in children with lower height-for-age Z-scores (HAZs). Despite early treatment and prolonged viral suppression, HIV-infected children had detectable mitochondrial impairment, particularly among those with stunted growth. Further study is required to determine if continued treatment will lead to full recovery of mitochondrial function in HIV-infected children.